The family Anelloviridae includes Torque teno viruses (TTV), TT-midiviruses (TTMDV) and TT-miniviruses (TTMV), the majority originating from samples of human origin (Nishizawa et al., 1997; Takahashi et al., 2000; Ninomiya et al., 2007; Okamoto, 2009; Biagini and de Micco, 2010). The plurality of this family of ssDNA viruses is reflected not only in DNA sequence, but also in genome size and organization.
Multiple attempts have been made to find a suitable in vitro system for the replication and propagation of TT viruses. Replicative forms of its DNA have been demonstrated in bone marrow cells and in the liver (Kanda et al., 1999; Okamoto et al., 2000a, c, d). Peripheral blood acts as reservoir for TT viruses (Okamoto et al., 2000b) and replication in vivo seems to occur preferably in activated mononuclear cells (Maggi et al., 2001b; Mariscal et al., 2002; Maggi et al., 2010). Although in vitro transcription has been investigated in a variety of cell lines (Kamahora et al., 2000; Kamada et al., 2004; Kakkola et al., 2007; 2009; Qiu et al., 2005; Müller et al., 2008), long term replication leading to virus production has been difficult to achieve (Leppik et al., 2007).
The presence of a variety of intragenomic rearranged TT subviral molecules in sera samples and the in vitro transcription of a subviral molecule constituting only 10% of the complete genome, initiated the discussion whether TT viruses may share similarities to the plantvirus family Geminiviridae (Leppik et al., 2007; de Villiers et al., 2009). Both mono- and bipartite Geminiviruses associate with single-stranded DNA satellites to form disease-inducing complexes (Saunders et al., 2000; Stanley, 2004; Nawaz-ul-Rehman and Fauquet, 2009; Jeske 2009; Paprotka et al., 2010; Patil et al., 2010).
Infections occur within the first days of life with close to 100% of infants being infected at one year of age. The primary route of infection however still remains unclear (Kazi et al., 2000; Peng et al., 2002; Ninomiya et al., 2008). The ubiquitous nature of TTV infections has hampered efforts to associate it with the pathogenesis of disease (Jelcic et al., 2004; Leppik et al., 2007; de Villiers et al., 2009; Okamoto, 2009). A possible etiological association with diseases of the liver (reviewed in Okamoto, 2009), respiratory tract (Biagini et al., 2003; Maggi et al., 2003a,b; Pifferi et al., 2005), hematopoietic malignancies (Jelcic et al., 2004; Leppik et al., 2007; de Villiers et al., 2002; 2009; Shiramizu et al., 2002; Garbuglia et al., 2003; zur Hausen and de Villiers, 2005) and auto-immune diseases (Sospedra et al., 2005; Maggi et al., 2001a; 2007; de Villiers et al., 2009) have been reported. During the past years, additional data has been compiled indicative of an association of TT virus infection with human malignant tumors. A high rate of TT virus load has been noted in a spleen biopsy of a patient with Hodgkin's lymphoma (24 individual TTV genotypes). Similarly, other reports describe a higher rate of TTV prevalence in colorectal and esophageal cancer and in hematopoietic malignancies in comparison to non-tumorous tissue from the same or other patients. Yet, the ubiquity of these infections rendered an interpretation of these results rather difficult and did not permit a linkage of these observations with tumor development.
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